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桓兴医讯 黑色素瘤患者对于CTLA-4阻滞剂临床反应的基因基础
文章来源:北京市朝阳区桓兴肿瘤医院 点击数: 发布时间:2014-12-05 08:54
《新英格兰杂志》2014年12月4日在线先发
黑色素瘤患者对于CTLA-4阻滞剂临床反应的基因基础
背景
免疫检测点抑制剂对于癌症治疗是有效的,但是临床获益的分子决定因素不清楚。Ipilimumab 和tremelimumab单抗是抑制细胞毒T淋巴细胞抗原4的抗体(CTLA-4),抗CTLA-4治疗延长黑色素瘤患者的总体生存。CTLA-4阻滞剂激活T细胞,从而能够使他们破坏肿瘤细胞。
方法
我们收集了ipilimumab 或者 tremelimumab.治疗的黑色素瘤患者的肿瘤组织,对肿瘤组织和匹配的血样本进行整个外显子组测序,机体突变和突变产生的新抗原给予特征定义,在ipilimumab治疗的患者中检测新生抗原肽类激活淋巴细胞的能力。
结果
根据大规模平行测序, 64例接受CTLA-4阻滞剂治疗的恶性黑色素瘤患者的外显子给予特征定义,这一组发现包括11例患者获得长期临床获益,和14例患者获得微小获益或没有获益。突变负荷和临床获益的程度相关(P=0.01),但是作为单独预测获益因素还不充分。利用全基因组新生抗原抗体结合位点分析和患者特异的HLA类型,我们对每位患者鉴定了所选肿瘤的新生抗原,阐明了对于CTLA-4阻滞剂强反应的肿瘤组织中特异性呈现的新生抗原的全景。我们在其余39例接受抗CTLA-4抗体治疗的黑色素瘤患者中验证了这种信号,预测ipilimumab.治疗的患者中新生抗原激活T细胞。
结论 这一发现定义了黑色素瘤从CTLA-4 阻滞剂获益的基因基础,对于正在考虑接受抗CTLA-4 因子治疗的患者如何检测外显子提供了理论基础。
北京桓兴肿瘤医院 桓兴医讯编译组 李淑娈
2012年12月4日 星期四
N Engl J Med 2014; 371:2189-2199December 4, 2014DOI: 10.1056/NEJMoa1406498
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
BACKGROUND
Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.
METHODS
We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.
RESULTS
Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti–CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.
CONCLUSIONS
These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti–CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.)

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